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WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau

PCT

INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(51) International Patent Classification 6
BOIL 3/00

(11) International Publication Number: WO 98/05424

(43) International Publication Date: 12 February 1998 (12.02.98)

(21) International Application Number: PCI7US97/13178

(22) International Filing Date: 3 1 July 1997 (3 1 .07.97)

(30) Priority Data:
08/691,632

2 August 1996 (02.08.96)

(60) Parent Application or Grant
(63) Related by Continuation
US

Filed on

08/691,632 (CIP)
2 August 1996 (02.08.96)

(71) Applicant (for alt designated States except US): CALIPER

TECHNOLOGIES CORPORATION [US/US]; 1275 Cali-
fornia Avenue, Palo Alto, CA 94304 (US).

(72) Inventor; and

(75) Inventor/Applicant (for US only): CHOW, Calvin, Y., H.
[US/US]; 455 Minoca Road, Portoia Valley, CA 94028
(US).

(74) Agents: HESLIN, James, M. et al.; Townsend and Townsend
and Crew LLP, 8th floor, Two Embarcadero Center, San
Francisco, CA 94111-3834 (US).

(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
GH, HU, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR,
LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ,
PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR,
TT, UA, UG, US, UZ, VN, YU, ZW, ARIPO patent (GH,
KE, LS, MW, SD, SZ, UG, ZW), Eurasian patent (AM, AZ,
BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE,
CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL,
PT, SE), OAPI patent (BF, BJ, CF, CG, CT, CM, GA, GN,
ML, MR, NE, SN, TD, TG).

Published

With international search report.

(54) Title: ANALYTICAL SYSTEM AND METHOD
(57) Abstract

An analytical or preparatory system comprises as a base
unit (12), an adapter (14), and a substrate (16). The adapter
(14) is attached to an attachment region on the base unit (12),
and the substrate (16) is attached to an attachment region on
the adapter (14). The adapter (14) permits the base unit (12)
to be interfaced with a wide variety of different substrates
(16) to perform chemical and biological analytical analyses and
preparatory procedures.

60 M

•18

42 «.

-22

FOR THE PURPOSES OF INFORMATION ONLY
Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.

Albania

Spain

Lesotho

Slovenia

Armenia

Finland

Lithuania

Slovakia

Austria

France

Luxembourg

Senegal

Australia

Gabon

Latvia

Swaziland

Azerbaijan

United Kingdom

Monaco

Chad

Bosnia and Herzegovina

Georgia

Republic of Moldova

Togo

Barbados

Ghana

Madagascar

Tajikistan

Belgium

Guinea

The former Yugoslav

Turkmenistan

Burkina Faso

Greece

Republic of Macedonia

Turkey

Bulgaria

Hungary

Mali

Trinidad and Tobago

Benin

Ireland

Mongolia

Ukraine

Brazil

Israel

Mauritania

Uganda

Belarus

Iceland

Malawi

United States of America

Canada

Italy

Mexico

Uzbekistan

Central African Republic

Japan

Niger

Viet Nam

Congo

Kenya

Netherlands

Yugoslavia

Switzerland

Kyrgyzstan

Norway

Zimbabwe

C6te d'T voire

Democratic People's

New Zealand

Cameroon

Republic of Korea

Poland

China

Republic of Korea

Portugal

Cuba

Kazakstan

Romania

Czech Republic

Saint Lucia

Russian Federation

Germany

Liechtenstein

Sudan

Denmark

Sri Lanka

Sweden

Estonia

Liberia

Singapore

WO 98/05424

PCI7US97/13178

ANALYTICAL SYSTEM AND METHOD

This application is a continuation-in-part of
Application No. 08/691,632, filed on August 2, 1996, the full
disclosure of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION
1. Field of the Invention

The present invention relates generally to systems
and methods for performing chemical and biological analyses .
More particularly, the present invention relates to the design
and use of an analyzer system which employs analytical
substrates evaluated in a base unit, where an adapter is used
as an interface between the substrate and the base unit.

Numerous systems and instruments are available for
performing chemical, clinical, and environmental analyses of
chemical and biological specimens. Conventional systems may
employ a variety of detection devices for monitoring a
chemical or physical change which is related to the
composition or other characteristic of the specimen being
tested. Such instruments include spectrophotometers,
f luorometers, light detectors, radioactive counters,
magnetometers , galvanometers , ref lectometers , ultrasonic
detectors, temperature detectors, pressure detectors,
mephlometers , electrophoretic detectors, PCR systems, LCR
systems, and the like. Such instruments are often combined
with electronic support systems, such as microprocessors,
timers, video displays, LCD displays, input devices, output
devices, and the like, in a stand-alone analyzer. Such
analyzers may be adapted to receive a sample directly but will
more usually be designed to receive a sample placed on a
sample -receiving substrate, such as a dipstick, cuvette,
analytical rotor, or the like. Usually, the sample- receiving
substrate will be made for a single, use (i.e. will be
disposable) , and the analyzer will include the circuitry,

WO 98/05424 PCT7US97/13178

optics, sample manipulation, and other structure necessary for
performing the assay on the substrate. As a result, most
analyzers are intended to work only with a single type of
sample-receiving substrate and are not readily adaptable to be
5 used with other substrates.

Recently, a new class sample-receiving substrate has
been developed, referred to as "microf luidic" systems.
Microfluidic substrates have networks of chambers connected by
channels which have mesoscale dimensions, where at least one

10 dimension is usually between 0.1 pirn and 500 pirn. Such
microfluidic substrates may be fabricated using
photolithographic techniques similar to those employed in the
semiconductor industry, and the resulting devices can be used
to perform a variety of sophisticated chemical and biological

15 analytical techniques. Microfluidic analytical technology has
a number of advantages, including the ability to employ very
small sample sizes, typically on the order of nanoliters. The
substrates may be produced at a relatively low cost, and can
be formatted to perform numerous specific analytical

20 operations, including mixing, dispensing, valving, reactions,
and detections.

Because of the variety of analytical techniques and
potentially complex sample flow patterns that may be
incorporated into particular microfluidic test substrates,

25 significant demands may be placed on the analytical units

which support the test substrates. The analytical units not
only have to manage the direction and timing of flow through
the network of channels and reservoirs on the substrate, they
may also have to provide one or more physical interactions

30 with the samples at locations distributed around the

substrate, including heating, cooling, exposure to light or
other radiation, detection of light or other emissions,
measuring electrical/electrochemical signals, pH, and the
like. The flow control management may also comprise a variety

3 5 of interactions, including the patterned application of
voltage, current, or power to the substrate (for
electrokinetic flow control), or the application pressure,

WO 98/05424 PCT/US97/13178

acoustic energy or other mechanical interventions for
otherwise inducing flow.

It can thus be seen that a virtually infinite number
of specific test formats may be incorporated into microfluidic
test substrates. Because of such variety and complexity, many
if not most of the test substrates will require specifically
configured analyzers in order to perform a particular test.
Indeed, it is possible that particular test substrates employ
more than one analyzer for performing different tests. The
need to provide one dedicated analyzer for every substrate and
test, however, will significantly reduce the flexibility and
cost advantages of the microfluidic systems.

It would therefore be desirable to provide improved
analytical systems and methods which overcome or substantially
mitigate at least some of the problems set forth above. In -
particular, it would be desirable to provide analytical
systems including base analytical units which can support a
number of . different microfluidic or other test substrates
having substantially different flow patterns, chemistries, and
other analytical characteristics. It would be particularly
desirable to provide analytical systems where the cost of
modifying a base analytical unit to perform different tests on
different test substrates is significantly reduced.

2 , Description of the Background Art

Microfluidic devices for analyzing samples are
described in the following patents and published patent
applications: U.S. Patent Nos. 5,498,392; 5,486,335; and
5,304,487; and WO 96/04547. An analytical system having, an
analytical module which connects to an expansion receptacle of
a general purpose computer is described in WO 95/02189. A
sample typically present on an analytical rotor or other
sample holder, may be placed in the receptacle and the
computer used to control analysis of the sample in the module.
Chemical analysis systems are described in U.S. Patent Nos.
5,510,082; 5,501,838; 5,489,414; 5,443,790; 5,344,326;
5,344,349; 5,270,006; 5,219,526; 5,049,359; 5,030,418; and
4,919,887; European published applications EP 299 521 and EP 6

WO 98/05424 PCTAJS97/13178

031; and Japanese published applications JP 3-101752;
JP 3-094158; and JP 49-77693.

The disclosure of the present application is related
to the following co-pending applications, the full disclosures
of which are incorporated herein by reference, application no.
60/015498 (provisional), filed on April 16, 1996; application
no. 08/671,987, filed on June 28, 1996; application no.
08/671,986, filed on June 28, 1996; application no.
08/678,436, filed on July 3, 1996; and application no.
08/683,080, filed July 16, 1996.

SUMMARY OF THE INVENTION
The present invention overcomes at least some of the
deficiencies described above by providing analytical and
preparatory systems and methods which employ an adapter to
interface between a sample substrate and an analytical base
unit. The sample substrate is usually a microfluidic
substrate but could be any other sample substrate capable of
receiving test specimen (s) or starting material (s) for
processing or providing a detectable signal, where the base
unit manages sample flow, reagent flow, and other aspects of
the analytical and/or preparatory technique (s) performed on
the substrate. The adapter allows a single type of base unit,
i.e. a base unit having a particular configuration, to
interface with a large number of test and other substrates
having quite different configurations and to manage numerous
specific analytical and preparatory techniques on the
substrates with little or no reconfiguration of the base unit
itself.

The methods and apparatus will find use with both
analytical and preparatory techniques. By "analytical," it is
meant that the assay or process is intended primarily to
detect and/or quant itate an analyte or analytes in a test
specimen. By "preparatory," it is meant that the process is
intended primarily to produce one or more products from one or
more starting materials or reagents. The remaining
description relates mainly to the analytical methods and
devices, but for the most part, all technology described will

WO 98/05424 PCT/US97/13178

be equally useful for preparing materials for other subsequent
uses .

In a first aspect, the present invention provides an
analytical system comprising a base unit having an attachment
region with a base interface array including at least one
interface component therein. An adapter that is configured to
be removably attached to the attachment region of the base
unit and has an adapter-base interface array which also
includes an interface component. The adapter-base interface
array mates with the base interface array when the adapter is
attached to the base unit, and at least some of the interface
components in each of the arrays will couple or mate with each
other. The adapter further includes a sample substrate S
attachment region having an adapter -sample substrate interface
array therein. The adapter- sample substrate interface array
will usually also include at least one interface component
(but in some cases could act primarily to position interface
component (s) on the base units relative to interface
component (s) on the sample substrate). A sample substrate is
configured to be removably attached to the sample substrate
attachment region of the adapter and itself includes a sample
substrate interface array which usually includes at least one
interface component. The interface component (s) in the sample
substrate interface array will mate with corresponding
interface component (s) in the adapter- sample substrate
interface array and/or in the base interface array when the
sample substrate is attached to the sample substrate
attachment region.

By providing suitable interface components in each
of the interface arrays, power and/or signal connections may
be made between the base unit and the sample substrate in a
virtually infinite number of patterns. In some cases, the
base unit will provide only power and signal connections to
the adapter, while the adapter will provide a relatively
complex adapter- sample substrate interface array for managing
flow, other operational parameters, and detection on the
sample substrate. In other cases, however, the base interface
array on the base unit may be more complex, including for

WO 98/05424 PCT/US97/13178

example light sources, detectors, and/or high voltage power,
and the adapter will be less. sophisticated, often acting
primarily to position the sample substrate relative to
interface components on the base unit, channeling voltages,
and allowing direct communication between the base unit and
the sample substrate.

Exemplary interface components include electrical
power sources, analog signal connectors, digital signal
connectors, energy transmission sources, energy emission
detectors, other detectors and sensors, and the like. Energy
transmission sources may be light sources, acoustic energy
sources, heat sources, cooling sources, pressure sources, and
the like. Energy emission detectors include light detectors,
f luorometers, UV detectors, radioactivity detectors, heat
detectors (thermometers), flow detectors, and the like. Other
detectors and sensors may be provided for measuring pH,
electrical potential, current, and the like. It will be
appreciated that the interface components will often be
provided in pairs where a component in one array is coupled or
linked to a corresponding component in the mating array in
order to provide for the transfer of power, signal, or other
information. The interface components, however, need not have
such paired components, and often energy transmission sources
or emission detectors will be provided without a corresponding
interface component in the mating interface array.

The base unit, adapter and sample substrate will be
configured so that they may be physically joined to each other
to form the analytical system. For example, the attachment
region in the base unit may be a cavity, well, slot, or other
receptacle which receives the adapter, where the dimensions of
the receptacle are selected to mate with the adapter.
Similarly, the attachment region on the adapter may comprise a
receptacle, well, slot, or other space intended to receive the
sample substrate and position the substrate properly relative
to the adapter and or base unit. The sample substrate will
preferably employ mesoscale fluid channels and reservoirs,
i.e. where the channels have at least one dimension in the
range from 0.1 /xm to 500 ptm, usually from 1 jim to 100 pirn. The

WO 98/05424 PCT/US97/13178

present invention, however, is not limited to the particular
manner in which the base unit, adapter, and substrate- are
attached and/or to the particular dimensions of the flow
channels on one sample substrate.

Although described thus far as a three-tiered
system, it should be understood that the additional components
or "tiers" could be utilized. For example, additional
carriers or adapters could be utilized for providing
additional interface (s) , such as a carrier for the sample
substrate, where the carrier would be mounted within or
attached to the adapter which is received on the base unit.
Similarly, the attachment region in the base unit which
receives the adapter may comprise a discrete component which
is itself removably or permanently affixed to the base unit.
Formation of the attachment region using a discrete component
is advantageous since it facilitates standardization of the
system. For example, the adapter- attachment region component
could be manufactured separately, optionally at a single
location, and/or otherwise prepared to strict specifications,
both of which would help assure that the base units which
incorporate such standardized attachment regions will be
compatible with all corresponding adapters. The standardized
adapter-attachment region could also be adapted to
interconnect with other components of the base unit, such as
heaters, cooling blocks, pin connections, and the like, thus
facilitating interface with these elements. Thus, systems
having four or more tiers fall within the scope of the present
invention.

In a second aspect of the present invention, the
analytical system comprises a base unit and a sample
substrate, generally as described above. An adapter is
configured to be removably attached to the attachment region
of the base unit and includes an attachment region to
removably receive the sample substrate. The adapter holds the
sample substrate in a fixed position relative to the base unit
and provides either (i) a connection path from an interface .
component in the base interface array to the substrate or (ii)
a connection path from an interface component in the sample

WO 98/05424 PCT/US97/13178

substrate array to the base unit. In this aspect of the
present invention, the adapter can act primarily to position a
sample substrate relative to the interface array in the base
unit. For example, if the base unit interface array includes
5 a light source and/or light detector, the adapter can properly
position the sample substrate relative to the light
source/detector in order to perform a desired measurement.
The adapter could optionally but not necessarily provide
further interface capabilities between the sample substrate
10 and the base unit.

In yet another aspect of the present invention,
adapters are provided for use in combination with base units
and sample substrates, as described above. The adapter
comprises an adapter body having an adapter-base interface
15 array including at least one of power and signal connector (s)
disposed to mate -with corresponding connector (s) in the base
interface array when the adapter is attached to the attachment
region on the base unit. The adapter further includes a
sample substrate attachment region having an adapter- sample
substrate interface array including at least flow biasing
connectors disposed to mate with corresponding regions in the
sample substrate interface array when the sample substrate is
attached to the attachment region of the adapter. The flow
biasing connectors will commonly be electrodes for
25 electrokinetic flow control in mesoscale and other

microfluidic sample substrates, but could also be acoustic,
pressure, or mechanical flow-producing components. The
adapter- sample substrate interface array will frequently
include interface components in addition to the flow biasing
30 connectors, such as radiation emission and detection

components positioned to interface with particular regions of
the sample substrates.

The base unit may be self-contained, i.e. it may
include all digital and/or analog circuitry as well as user
35 input /output interfaces which are necessary for controlling an
assay and producing assay results from the system. Often,
however, it will be preferable to interface the base unit with
a general purpose or conventional computer, where the computer

WO 98/05424 PCT/US97/13178

can provide some or all of the control analysis, and/or
reporting function (s) as well as some or all of the user
interface. Usually, the computer will be a standard personal
computer or workstation which operates on a standard operating
system, such as DOS, Windows® 95, Windows® NT, UNIX,
Macintosh, and the like. The computer will be able to provide
a number of standard user input devices, such as a keyboard,
hard disk, floppy disk, CD reader, as well as user outputs,
such as screens, printers, floppy disks, writable CD output,
and the like. . Use of the computer is particularly
advantageous since it can significantly reduce the cost of the
base unit and allow significant upgrading of the computer
component of the system while using the same base unit.
Despite these advantages, in some instances it may be
desirable to incorporate the interface and digital circuitry
of a computer into the base unit of the present invention,
allowing all of the capabilities of a conventional digital
computer,, but with perhaps less flexibility.

When the system of the present invention is
controlled via digital circuitry, i.e. using a separate
conventional computer interfaced with the base unit or using
digital control circuitry incorporated within the base unit,
it will usually be desirable to provide at least a portion of
the operating instructions associated with any particular
adapter and/or any particular sample substrate and assay
format in a computer -readable form, i.e. on a conventional
computer storage medium, such as a floppy disk, a compact disk
(CD ROM) , tape, flash memory, or the like. The medium will
store computer readable code setting forth the desired *
instructions, where the instructions will enable the computer
(which may be a separate or integral computer) to interface
with the base unit and to control an assay performed by the
base unit upon the sample present on a sample substrate held
by an adapter received on the base unit. The present
invention thus comprises the computer program itself in the
form of a tangible medium, e.g. disk, CD, tape, memory, etc.,
which may be used in combination with the system of the
present invention. The present invention further comprises

WO 98/05424 PCTAJS97/13178

systems which include an adapter as set forth above in
combination with the tangible medium storing the computer
instructions described above. The present invention still
further comprises systems which are combinations of one or
more sample substrates as generally set forth above, together
with a tangible medium setting forth computer readable code
comprising instructions as set forth above.

The computer program may be provided to the user
pre-loaded onto the desired medium, usually a floppy disk or a
CD ROM, or may alternatively be downloaded onto the medium by
the user from a central location via a network, over phone
lines, or via other available communication and transmission
means. The program will then be incorporated onto the medium
and be available for use in the systems and methods of the
present invention.

In a still further aspect in the present invention,
a method for configuring an analytical system comprises
providing a base unit having an attachment region including at
least one interface component therein. An adapter is
removably attached to the attachment region of the base unit
so that an interface component on the adapter mates with a
corresponding interface component on the base unit . The
adapter includes a sample substrate attachment region having
at least one interface component therein, and a sample
substrate is removably attached to the sample substrate
attachment region on the adapter so that an interface
component on the sample substrate mates with a corresponding
interface component on the adapter. Usually, but not
necessarily, the adapter is removably attached to the base
unit by placing the adapter within a receptacle on the' base
unit, and the sample substrate is removably attached to the
adapter by placing the sample substrate within a receptacle on
the adapter. The sample substrate will preferably be a
microfluidic device having a plurality of channels connecting
a plurality of reservoirs and including flow biasing regions
positioned at one of the reservoirs and/or channels. The base
unit may then direct or manage flow in the substrate by
providing flow control signals to the adapter. The flow

WO 98/05424 PCT/US97/13178

control signals energize flow biasing regions on the adapter
whereby corresponding flow biasing regions on the substrate
are energized to control flow through the channels and among
the reservoirs. For example, the flow control may be effected
by electrically biasing electrodes on the sample substrate to
cause electrokinetic flow control. Alternatively, the
energizing step may comprise acoustically driving the flow
biasing regions on the sample substrate. Usually, the adapter
will include electromagnetic radiation sources and detectors
for signal generation and detection in a variety of analytical
techniques . Any of the above control steps may be implemented
by providing computer- readable code to an integral or separate
computer which controls the analytical system.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 .illustrates a first embodiment of an
analytical system incorporating the features of the present
invention.

Fig. 2 illustrates a second embodiment of an
analytical system incorporating the features of the present
invention.

Fig. 3 is a block diagram illustrating the
information flow between various components of .the system of
the present invention.

Fig. 4 illustrates an exemplary analytical system
incorporating the components of the system of the present
invention.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS
Analytical systems according to the present
invention comprise a base unit, an adapter, and a sample
substrate. Each of these parts of the system will be
described in detail below. In general, the analytical systems
will be configured to receive and analyze a wide variety of
samples and specimens. For example, samples may be biological
specimens from a patient, but they may also be a wide variety
of other biological, chemical, environmental, and other
specimens having a component to be characterized or analyte to

WO 98/05424 PCT/US97/13178

be detected. The analytical systems may be used to implement
numerous specific analytical and/or preparative techniques,
such as chromatography, PCR, LCR, enzymatic reactions,
immunologic reactions, and the like. Samples will usually be
5 liquid or be liquified prior to testing, and will frequently
undergo a chemical or biochemical reaction prior to analysis.
The analytical systems may provide for a variety of
manipulations of the sample in addition to chemical and
biological reactions, such as mixing, dispensing, valving,

10 separation, heating, cooling, detection, and the like. The
analytical systems may rely on numerous known detection
techniques such as spectrophotometry, fluorometry, radiometry,
magnatometry, galvanometry, ref lectrometry , ultrasonic
detection, mephlometry, electrophoretic measurement,

15 temperature measurement, pressure measurement, potent iometric
measurement, amperometric measurement, and the like. In the
exemplary and preferred embodiments below, sample manipulation
and detection are performed in microfluidic substrates where
the sample is manipulated between and among very small volume

20 reservoirs and flow channels formed in the substrate.

Usually, all flow and test conditions on the substrate will be
controlled through the base unit and the adapter, as described
in more detail below.

The base unit of the present invention will

25 typically comprise an enclosure or frame which may be intended
for mounting, e.g. on the floor, on a counter, in a rack, or
in any other conventional manner, or which may be portable or
hand-held. The base unit will usually include at least power
and/or signal transmission circuits, and will usually include

3 0 signal processing capability for helping to analyze and/or
store data received from the adapter as described in more
detail below. The base unit will usually further include a
microprocessor for helping manage both its substrate
management and data collection duties. Optionally,

35 information displays in the form of video monitors,

alphanumeric displays, printers, LED displays, and the like,
may be provided on or in the frame, often together with data
entry devices, such as keyboards, touch screens, and the like.

WO 98/05424 PCT/US97/13178

In the exemplary embodiments, however, the base unit includes
only a plug connector for interfacing with an external
computer, where the computer provides the necessary input and
output devices. In such cases, the base unit will often, but
not necessarily, include an internal microprocessor for
controlling or helping to control the internal operations of
the base unit and adapter. Alternatively, a microprocessor
could be provided in the adapter, with the base unit providing
only interface functions between the adapter and the computer.
In other cases, all control functions will be managed through
the separate computer with the base unit and adapter providing
only distribution and interface functions . Again, it should
be appreciated that availability of both the base unit and the
adapter provides for a very wide range of specific designs
with different functions being selectively distributed between
the adapter and the base unit for particular assays and sample
substrate designs.

The base unit will include an attachment region for
removably securing the adapter. The attachment region on the
base unit has a base interface array including at least one,
and usually multiple, interface component (s) intended to
provide power and/or information communication with the
adapter. The interface component (s) comprise a wide variety
of devices as described in more detail below. The attachment
region may be any feature or structure on the enclosure or
frame of the base unit which can removably attach the adapter.
The attachment region will usually be constructed so that the
adapter can be connected in a unique configuration only so
that the base interface array will be uniquely configured
relative to the adapter. The attachment region may have a
wide variety of forms, such as receptacles, wells, slots,
trays (similar to a CD tray), or the like. Often, the
attachment region will define a receptacle having dimensions
which correspond to the outer peripheral dimensions of the
adapter so that the adapter may be held in a desired
orientation relative to the base unit. Alternatively, or in
addition, pegs, pins, latches, or other attachment elements

WO 98/05424 PCT/US97/13178

may be provided to hold the adapter on the base unit in a
desired orientation.

The adapter will also comprise an enclosure or
frame, although the enclosure or frame will usually be
significantly smaller than that of the base unit. The
enclosure or frame will be adapted to be received on or in the
attachment region of the base unit, as generally discussed
above, and will itself include an attachment region for
removably securing the sample substrate. The attachment
region on the adapter may take any of the forms discussed
above for the attachment region on the base unit, and it will
usually be necessary for the attachment region to immobilize
the sample substrate in a particular orientation relative to
the adapter.

The adapter will include an adapter-base interface
array which meets with or couples to the base interface array
when the adapter is mounted in the attachment region on the
base unit. The adapter-base interface array will include at
least one interface component which mates with a corresponding
interface component within the base interface array, usually
to provide for power and/or signal connection between the base
unit and the adapter. The interface component (s) may provide
for a wide variety of additional interconnections, and will be
described in greater detail below.

The sample substrate attachment region will include
an adapter- sample substrate interface array intended to mate
with or couple to a sample substrate interface array on the
sample substrate when the sample substrate is attached to the
attachment region. The adapter- sample substrate interface
array will itself include at least one interface component
which may be any of the components described in more detail
below. Usually, the adapter -sample substrate interface array
will include multiple interface components which are disposed
or distributed in a pattern selected to mate with at least
some corresponding interface component in the sample substrate
array on the sample substrate.

The sample substrate may comprise any one of a
variety of known analytical devices or articles intended for

WO 98/05424 PCT/US97/13178

receiving a sample and processing the sample in some manner to
provide a detectable output which can be related to a sample
characteristic, e.g. the presence of an analyte, the
composition or nature of a molecule present in the sample
(e.g. protein or nucleic acid sequence), or the like. The
present invention is particularly intended for use with
microfluidic sample substrate of the type described in U.S.
Patent Nos . 5,498,392; 5,486,355; 5,304,487; and published PCT
application WO 96/04547, the full disclosures of which are
incorporated, herein by reference. Suitable microfluidic
substrates are also described in commonly assigned co-pending
pending Application Nos. 08/761,987, filed June 28, 1996, and
08/845,759, filed April 25, 1997, the full disclosures of S
which are incorporated herein by reference.

A particular advantage of the present invention is
that the adapter .can be configured to receive any one of a
variety of specific sample substrate configurations. In that
way/ the designer of the sample substrate is free to optimize
the size, design, flow paths, and other features of the sample
substrate without undue regard to the nature of the base unit.
Within a wide latitude, most specific design features of a
sample substrate may be accommodated by appropriately
designing an adapter. While this advantage is available, it
is also possible that the design of the sample substrate take
into account specific characteristics and design features of
either or both of the base unit and adapter. It will be
appreciated that the system architecture employing the adapter
as an interface between the sample substrate and the base unit
provides for significant design flexibility.

The sample substrate will have dimensions and other
characteristics selected to permit removable attachment to the
attachment region, as generally discussed above. Sample
substrate will further include the substrate interface array
which includes at least one interface component disposed to
mate with a corresponding interface component on the adapter -
sample substrate interface array on the adapter. Again, the
interface components may comprise any of a wide variety of
particular devices and elements, as discussed in more detail.

WO 98/05424 PCT/US97/13178

The interface components on the adapter and sample substrate
will generally be able to provide for both flow control
management of the sample and other liquid reagents present in
and applied to the sample substrate and will further provide
5 for interconnection of power and signals between the adapter
and sample substrate.

As used herein and in the claims, the phrase
"interface component" refers to any one of a wide variety of
discrete components or regions present in the interface arrays

10 on the base unit, adapter, or sample substrate. Interface
components will generally provide for electrical or other
energy transfer, analog or digital signal transfer, energy
transmission, energy emission detection, and the like.

Electrical connections, both for power and signal

15 transfer, will generally comprise conventional connectors in
the form of electrodes, pins, plugs, zero insertion force
(ZIF) connectors, and the like. Such electrical connections
will usually require mating connectors in two of the interface
arrays which are brought together when the system is put

20 together. The electrical connectors will often be present on
a surface or edge of the interface array so that corresponding
components will be engaged against each other when the adapter
is mounted in the base unit or the substrate is mounted on the
adapter. Similarly, surface or edge electrodes in the

25 adapter- sample substrate interface array may be provided to
mate with corresponding surface or edge electrodes on the
sample substrate. The electrodes on the sample substrate may
then be connected internally in the substrate to the desired
reservoirs or fluid flow channels in order to effect

30 electrokinetic flow control, as described in the previously

incorporated patents and patent applications. In other cases,
however, it will be desirable to provide interface components
in the adapter- sample substrate interface array which directly
contact the fluid to be electrokinetically controlled. For

35 example, probes or pins may be provided on the adapter which
will penetrate into open wells or through septums on the
sample substrate in order to permit direct contact and

WO 98/05424 PCT/US97/13178

application of electrical potential. A specific example of
such connectors are shown in Fig. 2 below.

The energy transmission sources will generally be
intended to either energetically excite a region on the test
substrate or provide energy to initiate fluid flow on the
sample substrate. The energy may take a wide variety of
forms, including light, such as visible light and UV light, .
acoustic energy, heat, cooling, pressure, mechanical energy,
electrical energy, and the like. In the case of sample
detection, the energy transmission source may be light or
other radiation intended to excite a species or label to be
detected. Heating/cooling may be provided to help effect or
condition a particular chemical reaction. Acoustic, pressure,
and mechanical energy may be provided to directly effect fluid
flow in channels of microfluidic sample substrates. It will
be appreciated that such energy transmission sources do not
necessarily have corresponding interface components in an
adjacent interface array. Instead, energy transmission will
often be directed generally at regions on the sample substrate
where energy is to be received.

Energy emission detectors may be provided, usually
on the adapter and/or the base unit, to detect energy emitted
from the sample substrate. For example, detection reactions
may result in the emission of light via fluorescence,
luminescence, radiation, or other energy emissions which need
to be detected and/or quantified in order to perform
particular analysis. The appropriate detection components may
be provided in the adapter and/or base unit, and the adapter
relied on to appropriately align the substrate the detectors.

A particular class of interface components employed
by the analytical system of the present invention are referred
to as "flow biasing connectors." Flow biasing connectors are
intended to identify those interface components which can
effect fluid flow on sample substrates, particularly on
microfluidic substrates having a network of flow channels and
reservoirs. For microfluidic substrates employing
electrokinetic flow management, the flow biasing connectors on
the adapter will usually be electrodes, probes, pins, or the

WO 98/05424 PCT/US97/13178

like distributed within or on the adapter sample substrate
interface array to mate with the network of flow channels and
reservoirs in the sample substrate as generally described
above and in the previously incorporated references. The
electrodes will usually have corresponding electrode terminals
present within the interface array on the sample substrate so
that the electrode terminals may be interconnected to
corresponding electrical connectors on the adapter- sample
substrate interface array on the adapter (or in rare cases on
the base interface array on the base unit) . In other cases,
as described above, the flow biasing connectors may be probes
or -pins on the adapter which are positioned to directly engage
fluids present on or in the sample substrate. For example, an
array of pins may be provided on a hinged lid or cover on the
adapter plate so that the sample substrate may be positioned
on the adapter and the lid cover thereafter closed in order to
penetrate the pins into open sample wells on the substrate.
The sample wells, of course, need not be open and could be
covered with any penetratable membrane or septum which is
pierced by the pins when the cover is closed. Other flow
biasing connectors include acoustic energy sources
(piezoelectric transducers) positioned within the adapter-
sample substrate interface array so that they engage the
sample substrate at positions intended to induce fluid flow
through the flow channels. Other flow biasing connectors
include pressure sources which can initiate flow by
pressurization, mechanical energy sources, which can effect
mechanical pumping of liquids through the flow channels, and
the like.

Referring now to Fig. 1, a first exemplary '
analytical system 10 constructed in accordance with the
principles of the present invention comprises a base unit 12,
an adapter 14, and a sample substrate 16. The base unit 12
includes a pin socket 20 for mating with a plug 22 on a bottom
surface of the adapter 14. A computer port 24 is provided for
mating with conventional serial or parallel inputs on general
purpose computers, such as personal computers, work stations,
and the like. Usually, the base 12 will include at least

WO 98/05424 PCT/US97/13178

signal processing and conditioning components, such as analog-
to-digital converters for receiving analog data from the
adapter 14 and converting that data to digital form for
transmission to the computer. In other cases, however, the
computer may be adapted to directly convert analog signals, to
digital data. The base unit 12 and/or adapter 14 could also
be provided with digital-to-analog converters for controlling
power, flow, or any other parameter directly from digital
signals from the computer. The adapter 14 may also include
internal microprocessor (s) for further data manipulation. The
adapter 14 may also include a power input, for either line AC
current and/or low voltage DC current (which may be provided
by a power supply in the base unit 12) . The pin socket 2 0
will usually provide for interface for both power and signal
exchange between the base unit 12 and the adapter 14 .
Locating pins 28 .are provided on an upper surface of the base
12 to engage locating holes 3 0 on the adapter 14. Thus, the
entire upper surface of the base unit 12 will provide the
attachment region for the adapter 14 while the pin socket 20
will generally provide the adapter-base interface array with
the individual pins providing the interface components .

A plug 22 comprises the adapter-base interface array
on the adapter 14. The plug 22 provides for both power and
signal connections to the base unit 12 and the adapter further
provides an optical source and detector 34 and a
heating/cooling element 36, both of which mate to particular
regions on the sample substrate 16, as described further
below. The adapter 14 further includes an edge connector 40
which includes a number of electrodes 42 which mate with
corresponding electrodes 44 on an edge of the sample substrate
16. The sample substrate 16 is removably attached to the
adapter 14 by sliding the substrate between a pair of guides
46 which are formed by parallel L-shaped channels on the upper
surface of the adapter 14. When the sample substrate 16 is
fully inserted between the guides 46 with the electrodes 44
received in the edge connector 40, a reaction site 50 on the
sample substrate 16 is aligned with the optical source of
detector 34 on the adapter 14 and a thermal treatment region

WO 98/05424 PCT/US97/13178

52 is aligned with the heater/cooler 36 on the adapter. Thus,
the optical source detector 34, heater/cooler 36, and edge
connector 4 0 comprise interface components in the attachment
region of the adapter 14 .
5 The sample substrate 16 comprises a plurality of

sample and reagent wells 60, each of which is coupled to an
electrode 44 in the interface array. In this way, sample flow
on the sample substrate can be controlled through the base
unit 12 and the adapter 14 to control power through the

10 electrodes 42. It will be appreciated that the power may be
provided directly by the base unit 12, in which case the
adapter 14 acts merely to distribute the power.
Alternatively, the base unit 12 may provide information to the
adapter, and the adapter 14 generate the power internally

15 which is distributed through the electrodes 42. In either
case, sample flow among the reservoirs and a flow channel
network 66 is controlled in a desired manner. A portion of
the sample and mixed reagents will flow through the
heating/cooling region 52, where it will be appropriately

20 treated. Again, the amount of heat or cooling supplied by

region 3 6 is provided and controlled by a combination of the
base unit 12 and adapter 14, where specific functions may be
provided by either of those two components. An output signal
resulting from one or more reactions is eventually read at the

25 reaction region 50 by the optical source/detector 34. Output
of the optical detector 34 will be passed back to the base
unit 12 through the pin socket 20 and male plug 22. The
optical detector will usually produce an analog signal, and
such analog signal may be converted to digital in any of the

30 adapter 14, base unit 12, or external computer (not shown) .

A second exemplary embodiment 100 of the analytical
system of the present invention is illustrated in Fig. 2. The
analytical system 100 includes a base unit 112, an adapter
114, and a sample substrate 116. The base unit 112, is

35 similar in many respects to base unit 12 in Fig. 1, and

includes locating pins 128, a pin socket 120, and a computer
port 124. Base unit 112, however, further comprises an
optical source/detector 134. This is different than the

WO 98/05424 PCT/US97/13178

analytical system 10, where the optical source/detector 34 was
provided as part of the adapter 14.

The adapter 114 comprises a plate 115 having an
aperture 117 in its center. When the adapter 114 is mounted
on the base unit 112, the aperture 117 will lie generally over
the optical source/detector 134. Adapter 114 further includes
a hinged cover 119 which is used to cover and position the
sample substrate 116 on top of the plate 115. When the sample
substrate 116 is positioned, and the hinge cover 119 closed, a
plurality of probes 121 on a lower surface of the cover will
penetrate into sample and reagent wells 160 on the sample
substrate 116. The wells 160 may be completely open or may be
covered by a penet ratable membrane or septum. The probes 121 y
will thus be immersed and in direct contact with the liquids
present in the wells 160. In that way, electrical biasing can
be provided in order to effect electrokinetic flow management
through the channel network 166 on the sample substrate 116.

The sample substrate 116 includes a reaction zone
150 which will usually be at least partly transparent or
translucent to permit light from the optical source detector
134 to reach the fluid in the region and to permit emitted or
detected light to leave the region. Such incident and emitted
light from region 150 will pass through the aperture 117 in
the adapter 114 so that it may be directly coupled to the
optical source/detector 134. Again, this is a. difference with
the analytical system 10 of Fig. 1 where detection was
performed directly between the adapter 14 and the sample
substrate 16.

It should be appreciated, that the exemplary
analytical systems 10 and 100 are intended to be
representative of a virtually infinite number of possible
system configurations. Use of an adapter 14 or 114 permits
the various power, signal, and other functions of the
analytical system to be included in any one of the adapter,
base unit, substrate, or external computer in virtually any
manner so that any particular analytical technique can be
optimally supported by the system.

WO 98/05424 PCT/US97/13178

Referring now to Fig. 3, a system 200 according to
the present invention can be configured in a wide variety of
ways. For example, a base unit 212 may comprise a single
monolithic instrument containing all control and analysis
components necessary for performing an assay (in combination
with adapter 214 and sample substrate 216) , needing only to be
connected to line current or other power source. The base
unit 212, however, will be connected to a general purpose
computer 220, e.g. a personal computer or work station, which
provides at least a portion of the input/output, control, and
computational functions of the system 200. The computer 220
may- be connected by any conventional connectors, typically
using serial or parallel input ports. The /C omputer will be
programmed using software 222, which may be in the form of any
15 conventional computer medium. The software will comprise

instructions for. all or a portion of the computer functions.
For example, the software may comprise the operating system
utilized in performing all assays using the system of the
present invention. Alternatively, the computer may utilized a
conventional operating system capable of controlling real time
functions, as set forth above. The system test software 222
will usually include system instructions which are general and
apply to many assays as well as system instructions which are
specific for any particular assay. The instructions may be
25 included in a single disk or other medium, or may be included
in multiple disks which may then be combined in a desired
manner for performing a particular assay. Alternatively, the
test software may be downloaded into the base unit and/or onto
a storage medium via a network, the internet, or otherwise as
30 set forth above. The system software will include functions
such as system initialization, assay format, computational
instructions, user/patient input instructions, and the like.

Thus, it can be seen, that the base unit 212 and
computer 220 will generally be useful for performing many
35 different types of assays, while the adapter 214 and sample

substrate 216 will be more specifically directed at particular
assay (s) . One type of adapter 214 may be compatible with
multiple sample substrates 216 intended for performing two or

WO9S/05424 PCT/US97/13178

more different assays, where the system test software 222 can
enable the adapter 214 and base unit 212 to properly interface
with the sample substrate 216. Systems according to the
present invention will thus further comprise the combination
of test hardware 222 with either an adapter 214, sample
substrate (s) 216, or both. That is, a user already possessing
a monolithic base unit 212 or combination base unit 212 and
computer 220, may later acquire the combination of system test
software 222 and adapter 214 intended to perform a particular
assay or assays. By then mounting the adapter 214 on the base
unit and loading the software 222 onto the computer 220/base
unit 212, the system will be configured to receive sample
substrates to analyze particular test specimens for the
desired analyte. Alternatively, when an adapter 214 is
suitable for two or more assays, the user may later acquire
the combination of test software 222 and sample substrate (s)
216 which enable the preexisting combination of computer 220,
base unit 212, and adapter 214 to perform a new assay. In
some cases, the combination of adapter 214, sample
substrate (s) 216, and system test software 222 will also be
provided to the user.

Referring now to Fig. 4, ah exemplary system 300
configuration is illustrated. The system 300 comprises a base
unit 312, an adapter 314, and a sample substrate 316.
Additionally, a universal adapter 320 is provided as a
discrete component for removable or permanent mounting onto
the base unit 312. The universal adapter 320 defines the
attachment region on the base unit 312 for receiving the
adapter 314. Base unit 312 provides system functions, such as
an optical source/detector 322 and a heater plate 324. The
universal adapter 320 is mounted over the heater plate 324
onto a support surface 326 of the base unit 312. The base
unit 312 is then ready to removably receive adapter plate (s)
314 which in turn is ready to receive sample substrates 316.
The various interfaces among the system components may follow
any of the patterns described above in connection with. the
systems of Figs. 1 and 2. Use of the universal adapter 320 is
advantageous since it facilitates standardization of the

WO 98/05424 PCT/US97/13178

interface between the base unit 312 and the adapter 314.
Also, a single base unit 312 (or base' unit design) can be
interfaced with an even wider range of adapters 314 by
employing different classes or types of universal adapters,
each of which can display alternative functionalities and
interconnection patterns.

Although the foregoing invention has been described
in some detail by way of illustration and example, for
purposes of clarity of understanding, it will be obvious that
certain changes and modifications may be practiced within the
scope of the appended claims.

WO 98/05424

WHAT IS CLAIMED IS :

PCT/US97/13178

1 1. A system for manipulating materials comprising:

2 a base unit having an attachment region with a base

3 interface array including at least one interface component

4 therein;

5 an adapter configured to be removably attached to

6 the attachment region and having an adapter-base interface

7 array including at least one interface component disposed to

8 mate. with a corresponding interface component in the base

9 interface array when the adapter is attached to the attachment

10 region, a substrate attachment region, and an adapter-

11 substrate interface array having at least one interface

12 component therein; and

13 a substrate configured to be removably attached to

14 the substrate attachment region of the adapter and having a

15 substrate interface array including at least one interface

16 component disposed to mate with a corresponding interface

17 component in the adapter-substrate interface array when the

18 substrate is attached to the substrate attachment region.

1 2 . An analytical system as in claim 1 wherein the

2 base interface array includes at least one interface component

3 selected from the group consisting of electrical power

4 sources, analog signal connectors, digital signal connectors,

5 energy transmission sources, electrical/electrochemical signal

6 detectors, pH detectors, and energy emission detectors.

1 3. An analytical system as in claim 1, wherein the

2 adapter- substrate array includes at least one interface

.3 component selected from the group consisting of electrical

4 power sources, analog signal connectors, digital signal

5 connectors, energy transmission sources, pH detectors, energy

6 emission detectors, and electrical/electrochemical signal

7 detectors.

WO 98/05424 PCT/US97/13178

1 4. An analytical system as in claim 1 or 2,

2 wherein the energy transmission sources are selected from the
group consisting of light sources, acoustic energy sources,

4 heat sources, cooling sources, and pressure sources.

1 5. An analytical system as in claim 1, wherein the

2 base unit comprises a digital processor.

1 6. An analytical system as in claim 1, wherein the

2 base interface array comprises at least electrical power

3 electrodes disposed to mate with electrical power electrodes
on the adapter-base interface array of the adapter and at

5 least electrical signal electrodes disposed to mate with

6 electrical signal electrodes on the adapter-base interface

7 array of the adapter, wherein said power electrodes provide

8 electrical power. to the adapter and said signal electrodes

9 provide data transmission between the base unit and the
10 adapter.

1 7. An analytical system as in claim 1, wherein the

2 attachment region on the base unit comprises a receptacle

3 formed in a surface of the base unit.

1 8. An analytical system as in claim 9, wherein the

2 receptacle has peripheral dimensions which mate with the

3 adapter.

1 9. An analytical system as in claim 7, further

2 comprising a latch on the base unit for securing the adapter

3 within the receptacle.

1 10. An analytical system as in claim 1, wherein the

2 attachment region on the base unit comprises a discrete

3 component which is attached to the base unit.

1
2
3

11. An analytical system as in claim 1, wherein the
substrate has a top side, a bottom side, and an interior
region therebetween, wherein the interior region has a

WO 98/05424 PCT/US97/13178

4 plurality of mesoscale channels connecting a plurality of

5 reservoirs and wherein the flow biasing elements comprise

6 electrode terminals exposed on an exterior surface of the

7 substrate and/or access points on the substrate which permit

8 probe penetration.

1 12. An analytical system as in claim 9, wherein the

2 substrate has openings over at least some of the reservoirs to

3 permit direct penetration by probes in the adapter-substrate

4 interface array.

1 13. An analytical system as in claim 11, wherein

2 the adapter- substrate interface array includes a multiplicity

3 of electrodes disposed in a pattern to mate with the exposed

4 electrode terminals on the substrate.

1 14. An analytical system as in claim 3, wherein the

2 adapter- substrate interface array includes at least one

3 additional interface component .

1 15. An analytical system as in claim 14, wherein

2 the additional component comprises an electromagnetic

3 radiation source and wherein the substrate includes a region

4 transparent to said electromagnetic radiation, wherein the

5 transparent region is aligned with the source when said

6 substrate is attached within the substrate attachment region

7 on the adapter.

1 16. An analytical system as in claim 15, further

2 comprising an electromagnetic radiation detector disposed

3 within the adapter- substrate interface array so that it will

4 receive emitted radiation from the transparent region when the

5 substrate is attached within the attachment region.

WO 98/05424 PCT/US97/13178

17. An analytical system as in claim 1, wherein the
attachment region on the adapter comprises a receptacle formed
in a surface of the adapter, said receptacle having peripheral
dimensions which correspond to outer peripheral dimensions of
the substrate .

18. An analytical system as in claim 17, further
comprising a latch on the adapter for securing the substrate
within the receptacle.

19. An analytical system as in claim 1, further
comprising a tangible medium storing computer readable code
comprising instructions, wherein said instructions enable a
computer to interface with the base unit and control an assay
performed by the base unit upon a present on a substrate held
by an adapter received on the base unit.

20. An analytical system comprising:

a base unit having an attachment region with a base
interface array including at least one interface component
therein;

a substrate having a interface array including at
least one interface component therein; and

an adapter configured to be removably attached to
the attachment region of the base unit and having an
attachment region to removably receive the substrate, wherein
the adapter holds the substrate in a fixed position relative
to the base unit and provides at least one of . (i) a connection
path from the interface component in the base interface array
to the substrate or (ii) a connection path from the interface
component in the substrate array to the base unit.

21. An analytical system as in claim 20, wherein
the adapter includes an energy distribution network, wherein
the interface component in the base interface array is an
energy source, and wherein the substrate array comprises a
plurality of energy connectors which couple to the energy
distribution network in the adapter.

WO 98/05424 PCT/US97/13178

1 22. An analytical system as in claim 20, wherein

2 the base interface array includes an energy emission detector,

3 wherein the substrate array includes an energy transmission

4 region, and wherein the adapter aligns the energy emission

5 detector with the energy transmission region when the adapter

6 is mounted on the attachment region of the base unit and the

7 substrate is mounted on the attachment region of .the adapter.

1 23. An adapter for use in combination with a base

2 unit having an attachment region with a base interface array

3 and a substrate having a substrate interface array, said

4 adapter comprising:

5 / an adapter body having an adapter-base interface

6 array including at least one of power and signal connector (s)

7 disposed to mate with corresponding connector (s) in the base

8 interface array when the adapter is attached to the attachment

9 region on the base unit and a substrate attachment region

10 having an adapter- substrate interface array including at least

11 flow biasing connectors disposed to mate with corresponding

12 regions in the substrate interface array when the substrate is

13 attached to the attachment region of the adapter .

1 24. An adapter as in claim 23, wherein the adapter

2 substrate interface array includes at least one additional

3 interface component selected from the group consisting of

4 electrical power sources, analog signal connectors , digital

5 signal connectors, energy transmission sources,

6 electrical/electrochemical signal detectors, pH detectors, and

7 energy emission detectors.

1 25. An adapter as in claim 24, wherein the

2 additional component comprises an electromagnetic radiation

3 source and wherein the substrate includes a region transparent

4 to said electromagnetic radiation, wherein the transparent

5 region is aligned with the source when said substrate is

6 attached within the substrate attachment region on the

7 adapter.

WO 98/05424 PCT/US97/13178

26. An adapter as in claim 25, further comprising
an electromagnetic radiation detector disposed within the
adapter- substrate interface array so that it will receive
emitted radiation from the transparent region when the
substrate is attached within the attachment region.

27. An adapter as in claim 23, wherein the
attachment region on the adapter comprises a receptacle formed
in a surface of the adapter, said receptacle having peripheral
dimensions which correspond to outer peripheral dimensions of
the substrate.

28. An adapter as in claim 27, further comprising a
latch on the adapter for securing the substrate within the
receptacle .

29. A system comprising:

an adapter as in claim 23; and

a tangible medium storing computer readable code
comprising instructions, wherein said instructions enable a
computer to interface with the base unit and control an assay,
performed by the base unit upon a present on a substrate held
by an adapter received on the base unit.

30. A system for use in combination with a
computer, a base unit having an adapter attachment region, arid
an adapter, said system comprising:

a substrate capable of receiving a to be analyzed
and adapted to be mounted on the adapter; and

computer readable code comprising instructions which
enable the computer to interface with the base unit and
control an assay performed by the base unit upon a present on
a substrate held by an adapter received on the base unit.

31. A computer program article for use in
combination with a computer, a base unit having an adapter
attachment region, an adapter having a substrate attachment
region, and a substrate capable of receiving a material to be

WO 98/05424 PCT/US97/13178

5 processed, said computer program article comprising a tangible

6 medium storing computer readable code comprising instructions,

7 wherein said instructions enable a computer to interface with

8 the base unit and control the process performed by the base

9 unit upon a present on the material substrate held by an
10 adapter received on the base unit.

1 32. A method for configuring an analytical system,

2 said method comprising:

3 providing a base unit having an attachment region

4 including at least one interface component therein;

5 removably attaching an adapter to the attachment

6 region of the base unit so that an interface component on the

7 adapter mates with a corresponding interface component on the

8 base unit, wherein the adapter includes a substrate attachment

9 region having at .least one interface component therein; and

10 removably attaching a substrate to the substrate

11 attachment region on the adapter so that an interface

12 component on the substrate mates with a corresponding

13 interface component on the adapter.

1 33. A method as in claim 32, wherein the adapter is

2 removably attached to the base unit by placing the adapter

3 within a receptacle in the base unit.

1 34. A method as in claim 32, wherein the substrate

2 is removably attached to the adapter by placing the substrate

3 within a receptacle in the adapter.

1 35. A method as in claim 32, wherein the substrate

2 has a plurality of channels connecting a plurality of .

3 reservoirs and flow biasing regions, positioned at at least

4 some of the reservoirs or channels . .

WO 98/05424 PCT/US97/13178

1 3 6. A method as in claim 35, further comprising:

2 directing flow control signals from the base unit to

3 the adapter; and

energizing flow biasing regions the adapter in
response to the flow control signals, whereby corresponding
flow biasing regions on the substrate are energized to control
7 flow through the channels and among the reservoirs.

1 37. A method as in claim 36, wherein the energizing

2 step comprises electrically biasing the flow biasing regions.

1 38. A method as in claim 36, wherein the energizing

2 step comprises acoustically driving the flow biasing regions.

1 3 9. A method as in claim 36, wherein the directing

2 and energizing steps comprise providing computer readable

3 instructions to a computer connected to the base unit.

1 40. A method as in claim 32, wherein the adapter

2 further comprises at least an electromagnetic radiation

3 source, said method further comprising directing an

4 electromagnetic radiation source control signal from the base

5 unit to the adapter.

1 41. A method as in claim 40, wherein the adapter

2 further comprises an electromagnetic radiation detector, said

3 method further comprising generating a signal in the adapter

4 in response to radiation emitted from the substrate and

5 directing said signal to the base unit.

1 42. A method as in claim 41, wherein the signal

2 generating step and the signal directing step comprise

3 providing computer readable instructions to a computer

4 connected to the base unit.

WO 98/05424

PCT/US97/13178

FIG. 1

SUBSTITUTE SHEET (RULE 26)

WO 98/05424

PCT/US97/13178

SUBSTITUTE SHEET (RULE 26)

WO 98/05424

PCT/US97/13178

3/4

200

TEST
SOFTWARE

222

220

COMPUTER

IN OUT

216

SAMPLE
SUBSTRATE

214

ADAPTER

212

BASE
UNIT

IN OUT
(OPTIONAL)

SAMPLE

FIG. 3

SUBSTITUTE SHEET (RULE 26)

WO 98/05424

PCT/US97/13178

4/4

FIG. 4

SUBSTITUTE SHEET (RULE 26)

TTVT T T r CT> KT A TT/~\M A T CTJADPU TJ T7Tjtf"\T>T'

IIN lr*KlNAllUINAJL ixLAKL.rl KJbrlJKI

Inten .ial Application No

PCT/US 97/13178

A. CLASSIFICATION OF SUBJECT MATTER

IPC 6 B01L3/00

According to International Patent Classification (IPC) or to both national classification and IPC

8. FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols)

IPC 6 BOIL

Documentation searched other than mlnimumdocumentatlon to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practical, search terms used)

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category •

Citation ol document, with indication, where appropriate, of the relevant passages

Relevant to claim No.

X
Y
Y
A

US 4 726 929 A (GROPPER ADRIAN ET AL) 23
February 1988

see column 2, line 30 - column 4, line 7

W0 95 02189 A (ABAY SA) 19 January 1995

cited in the application

see page 3, line 21 - page 11, line 11

US 5 519 635 A (MIYAKE RYO ET AL) 21 May
1996

see the whole document

EP 0 616. 218 A (HITACHI LTD) 21 September
1994

see the whole document

-/~

1-6,20,
23,32

1-42
1-42
1-42

(3 ™

her documents are listed In the continuation of box C. |X | Patent tomHy members are listed In annex.

• Special categories of cited documents : ^ ^ docum8nt pub , ton9(J aftG r the international filing date

or priority date and not In conflict with the application but
"A" document defining the general state of the art which is not c aad to understand the principle or theory underlying the

considered to be of particular relevance Invention
"E" earlier document but published on or after the International «x' document of particular relevance; the claimed Invention

filing date cannot be considered novel or cannot be considered to
V document which may throw doubts on priority dalm(s) or Involve an Inventive step when the document Is taken alone

which is cited to establish the publication date of another -y- document of particular relevance: the claimed Invention

citation or other speciaJ reason (as specified) cannot be considered to Invofve an Inventive step when the
XT document referring to an oral disclosure, use. exhibition or document is combined with one or more other such docu-

otherrneans menta, such combination being obvious to a person skilled
"P" document published prior to the International filing date but in the art.

lawman the priority date claimed document member of the same patent famrty

Oate of the actual completion of thelnternational search

14 November 1997

Oate of mailing of the international search report

24/11/1997

Name and mailing address of the ISA

European Patent Office, P.B. 581 8 Patentiaan 2
NL - 22B0 HV Rljswljk
TeU (431-70) 340-2040, Tx. 31 651 epo nl,
Fax (+31-70) 340-3016

Authorized officer

Blndon, C

Form PCT/1SA/210 <«ocond ihwi) (July 1 W2)

page 1 of 2

INTERNATIONAL SEARCH REPORT

Inten nal Application No

PCT/US 97/13178

C.(Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT

Category :

Citation of document, with Indicalioawhere appropriate, ol the relevant passages

Relevant to claim No.

WO 96 14934 A (UNIV PENNSYLVANIA) 23 May
1996

see the whole document

US 5 223 219 A (SUBRAMANIAN KUMAR ET AL)
29 June 1993

see column 2, line 36 - column 3, line 28

WO 95 26796 A (INTEGRATED CHEMICAL
SYNTHESIZE ;BARD ALLEN J (US)) 12 October
1995

see page 14, line 7 - page 20, line 8

1-42

1,20,32

Form PCT71SA/21 0 (oontfnu»don ol second sheat) (Jiiy 1 992)

page 2 of 2

INTERNATIONAL SEARCH REPORT

information on patent family members

Inter nai Application No

PCT/US 97/13178

Patent document
cited in search report

Publication
date

Patent family
member(s)

Publication
date

US 4726929 A 23-02-88 US RE33858 E 24-03-92

DE 3688142 A 06-05-93.

EP 0189316 A 30-07-86

JP 2575112 B 22-01-97

JP 61210959 A 19-09-86

W0 9502189 A 19-01-95 AU 7245094 A 06-02-95

US 5519635

21-05-96

7083935 A

• 31-03-95

EP 0616218

21-09-94

6265447 A

22-09-94

5480614 A

02-01-96

23-05-96

5587128 A

24-12-96

4236996 A

06-06-96

4282896 A

06-06-96

All

4282996 A

06-06-96

2181189 A

23-05-96

2181190 A

23-05-96

1143917 A

26-02-97

0739240 A

30-10-96

0739423 A

30-10-96

9615269 A

23-05-96

9614933 A

23-05-96

US 5223219

29-06-93

3976793 A

18-11-93

2109704 A

28-10-93

0593714 A

27-04-94

6509279 T

20-10-94

9320939 A

28-10-93

WO 9526796

12-10-95

5580523 A

03-12-96

2200195 A

23-10-95

2186896 A

12-10-95

0754084 A

22-01-97

Form PCT/tSA/210 (pttant twr*y «nmx) (Atfy 1992)

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